A growing number of studies have demonstrated that combinatorial approaches are providing a path for personalization of strategies to treat a wide array of disease states. While providing a promising path to revolutionize medicine, the evolution of personalized, minimally invasive, combinatorial therapies has been slowed as a result of technological limitations. As such, there is a pressing need for designing new devices to facilitate the development of paradigm changing, minimally invasive, approaches to treat diseased tissues in situ which enable trans-disciplinary strategies to combat disease. This Phase 2 project, which builds upon the success of the completed Phase 1, is designed to address this need through the development of a next generation flexible endoscopic compatible ablation catheter platform (FrostBite) for the treatment of various gastrointestinal cancers including pancreatic and liver cancer. This multi-functional platform will enable the application of multiple therapeutic and diagnostic approaches (pharmaceutical, ablation, among others) in a single device format which when combined with novel vitamin D3 analogs designed to increase the lethality of freezing, will provide for an enhanced treatment option for numerous cancers. The ability to deliver multi-parametric treatment regimens of the FrostBite catheter is enhanced by the incorporation of a novel deployable thermosensor to monitor ablation zone formation in real time. This, when combined with advanced imaging approach compatibility, including endoscopic ultrasound, MRI, and CT, will provide for unmatched control and visualization during a procedure. Phase 1 activities yielded a prototype 1.27mm needle tip catheter capable of delivering cryothermal insults to a target within 10 seconds creating a zone of destruction of ~2.5cm in less than 3 mins. Studies into combinatorial drug/thermal insults also demonstrated improved outcomes in tissue models. This Phase 2 is designed to 1) miniaturize and test the next generation endoscopic compatible cryocatheter, 2) integrate a novel in situ deployable multipoint thermal sensor to enable real time monitoring of the thermal profile of the target during ablation, 3) develop and evaluate a series of vitamin D3 analogs (commercial and novel), and test the optimal combination device and analog protocol in an ex vivo engineered tumor model and in in vivo studies. This project builds upon successful P1 studies, as well as others, and leverages the combined expertise of researchers from CPSI, University of Ottawa, Binghamton University, and Johns Hopkins School of Medicine to develop a new surgical device and adjunctive drug combination approach to more effectively treat cancers of the liver and pancreas. Once completed, this project will provide for an effective, minimally invasive treatment option for individuals suffering from these and other gastroenterological based cancers such as colorectal, stomach and esophageal cancer. Successful completion of this project will provide for a novel medical device enabling the development and application of advanced personalized treatment regimes for 100?s of thousands of patients who suffer from numerous gastrointestinal tissue disease states which are untreatable or inadequately treated with today?s state of the art devices yielding improved patient survival and quality of life.